U.S. Pat. No. 5,159,083 (Thurkauf et al., Assignors to Neurogen Corporation) describes and claims aminomethyl-phenylimidazole derivatives as a class of dopamine receptor subtype specific ligands. Similar compounds are described in PCT publications WO 92/12134 (which largely corresponds to U.S. Pat. No. 5,159,083), WO 96/10018 and WO 96/16040. Such compounds show promise in the treatment of psychoses such as schizophrenia, and also in the treatment of psychomotor disturbances such as Parkinsonism.
A subgroup of compounds covered by formula I of U.S. Pat. No. 5,159,083 comprises phenylimidazolylmethylpiperazines, and a particularly preferred compound of this type that is covered by formula I of U.S. Pat. No. 5,159,083 but not specifically disclosed therein is 5-fluoro-2-4-(2-phenyl-1H-imidazol-5-yl)methyl!-1-piperazinyl!pyrimidine , a compound having the formula A: ##STR1##
This compound is disclosed in WO 96/16040 as compound 58 on page 37 and (as its dihydrochloride) in Example 9 at page 55 lines 22-23, where an alternative name, 2-phenyl-4(5)-(4-(5-fluoro-2-pyrimidinyl)-piperazin-1-yl)methyl!-imidazol e, is given. Another preferred compound is the corresponding des-fluoro derivative, 2-4-(2-phenyl-1H-imidazol-5-yl)methyl!-1-piperazinyl!pyrimidine.
A general chemical method is described in the above-cited U.S. patent and PCT publications for the preparation of aminomethyl-phenylimidazole derivatives; in U.S. Pat. No. 5,159,083 it is shown in Scheme I across columns 11 and 12. The important steps (in relation to the process of the present invention) are those at the last arrow of Scheme I, namely the chlorination of the 5-hydroxymethyl-2-(optionally substituted phenyl)-1H-imidazole with thionylchloride to yield the corresponding 5-chloromethyl compound, which is then allowed to react with an amine to yield a desired aminomethyl-phenylimidazole, e.g., a phenylimidazolylmethylpiperazine. For the preparation of the compound of formula A, this can be shown in Scheme A as follows: ##STR2##
However, that process, especially as applied to the compound of the formula A, has a number of disadvantages:
1. The chloromethyl intermediate is unstable and reactive;
2. It is therefore difficult to purify, extremely so by recrystallization;
3. It is consequently difficult to scale up the processes for its preparation and further conversion;
4. Its condensation with 5-fluoro-2-piperazinyl-pyrimidine proceeds in relatively low yield, especially in larger scale preparations;
5. The desired product, 5-fluoro-2-4-(2-phenyl-1H-imidazol-5-yl)methyl!-1-piperazinyl!pyrimidine , is not easy to purify from that process.
Another possible process for the preparation of compounds of this type comprises the fusion of compounds similar to the hydroxy compound of the formula B and the amino compound of the formula C in Scheme A above. This process is illustrated in WO 96/16040 in Scheme 3 on page 45 and in Example 39 (part B) for 2-4-(2-phenyl-1H-imidazol-5-yl)methyl!-1-piperazinyl!pyrimidine. However, this process affords only about an 80% yield of 2-4-(2-phenyl-1H-imidazol-5-yl)methyl!-1-piperazinyl!pyrimidine and consumes a large amount (two equivalents or more) of the compound of formula C; moreover, it does not afford a practical yield of the compound of the formula A itself.
Some of these disadvantages tend to apply similarly in the preparation of other compounds of this series.
Clearly, methods are needed that avoid or reduce these disadvantages and provide a process for the preparation of aminomethyl-phenylimidazoles that affords the final product in greater yield and purity, proceeds from an intermediate that is easier to handle, especially to purify, and is better suited to preparation on the commercial scale.